While the abuse potential of psychomotor stimulants has been well-demonstrated, there are marked differences across individuals in their response to the reinforcing and subjective effects of stimulants. Genetic factors are hypothesized to influence vulnerability to drug abuse and recent research suggests a greater prevalence of the D2 dopamine receptor A1 allele, in particular, among stimulant abusers. What has not been examined to our knowledge is how individuals, prospectively identified as DRD2 A1 allele carriers or noncarriers, may differ in their sensitivity to the reinforcing effects of stimulants. This proposal is submitted in response to NIDA's RFA DA-09-016, "Behavioral Pharmacology and Genetics: Translating and Targeting Individual Differences". The Primary Aim will be to prospectively investigate whether individuals with and without the allele differ in response to the classic psychomotor stimulant, d-amphetamine (d-AMP). Allele carriers (N=30) and noncarriers (N=30) will be recruited and complete baseline measures shown to be associated with vulnerability for drug abuse (e.g., demographics, impulsivity, sensation seeking). We will then use a human lab model to rigorously assess individual sensitivity to the reinforcing effects of d-AMP. Using a classic discrete-trial choice design shown in prior studies to demonstrate clear individual differences to the reinforcing effects of drugs, participants will have repeated opportunities to choose between d-AMP or placebo. Use of multiple d-AMP doses (5, 10, 20 mg/70 kg) will permit us to detect group differences more readily than a single dose would allow (e.g., shifts in dose-effect curves). We hypothesize that allele carriers will exhibit greater preference for d-AMP than noncarriers. Secondary Aim 1: We will examine associations between the other risk factors assessed at intake and allele status. We hypothesize that allele carriers will have elevated impulsivity and sensation seeking relative to noncarriers. Secondary Aim 2: Prior studies have retrospectively found a positive linear association between stimulant abuse severity and probability that an individual has the A1 allele. In secondary analyses, we will collapse subjects across allele status and examine choice data, hypothesizing a linear relationship between percent of d-AMP choices and probability that an individual has the allele. In summary, individuals vary widely in their response to psychomotor stimulants and these differences may be associated with their vulnerability to stimulant abuse. In the proposed study, we will prospectively examine whether d-AMP reinforcement varies as a function of DRD2 allele status. Knowledge gained from this study may benefit public health by advancing our understanding of individual differences in vulnerability to the reinforcing effects of psychomotor stimulants. Overall, the successful development of a human lab model for rigorously investigating individuals'vulnerability to the reinforcing effects of commonly-abused drugs would represent a significant step forward in our efforts to understand, prevent and treat drug abuse. PUBLIC HEALTH RELEVANCE: Individuals vary widely in their response to drugs and these differences may be associated with their vulnerability to drug abuse. In the proposed study, we will prospectively examine whether an individual's dopamine receptor genotype may predict their sensitivity to d-amphetamine reinforcement. Knowledge gained from this study may benefit public health by advancing our understanding of individual differences in vulnerability to the reinforcing effects of psychomotor stimulants and improving our efforts to understand, prevent and treat drug abuse more generally.